Approximately 1 in 2,000 women above the age of 50 develop primary biliary cirrhosis (PBC). There is no cure for this progressive hepatobiliary disease, which is one of the major indications for liver transplantation in the US. About 95% of patients develop anti-mitochondrial antibodies (AMA) reactive to pyruvate dehydrogenase complex E2 component (PDC-E2), which is aberrantly expressed on cell surface of biliary epithelial cells of patients with PBC. This abnormal distribution of PDC-E2 is only observed in patients with PBC and considered a phenotypic manifestation of the disease. We have cloned an exogenous retrovirus from a PBC biliary epithelium cDNA library with homology to betaretroviruses. Most PBC patients have specific antibody reactivity to the virus by Western blot and evidence for infection in lymph nodes using RT-PCR and immunohistochemistry. Also, we have found that affinity purified AMA from PBC patient's serum react with the virus. To study the viral infection in vitro, we have developed a model for PBC by co-culturing normal biliary epithelium cells with perihilar lymph nodes from patients with chronic liver disease. The biliary epithelium cells incubated with PBC lymph node extracts express increased levels of PDC-E2 autoantigen after 5 days, which is a finding specific for the PBC co-cultures. The supernatants from the PBC co-cultures also induce PDC-E2 expression in fresh biliary epithelial cells, which can be abrogated by gamma irradiation. We have also demonstrated that the development of the PBC phenotype corresponds with betaretrovirus infection in the biliary epithelium cells and supernatants. In a pilot study of anti-retroviral therapy with Combivir, 40% of patients completely normalized their liver function tests and there was a significant reversal of ductopenia on liver biopsy. In order to test the hypothesis that a retrovirus is associated with PBC, we plan to isolate the retrovirus and use our in vitro model of PBC to demonstrate that the specific isolate induces the phenotypic manifestation of disease in normal biliary epithelial cells. We will then assess whether patients with PBC have serologic evidence for infection. We anticipate that our studies will help to further our knowledge of how viral infections can promote autoimmune disorders and provide alternative strategies to help manage PBC patients with anti-viral therapy or vaccination for susceptible individuals. [unreadable] [unreadable]